PROJECT SUMMARY AND ABSTRACT Gold nanoparticles have found promising applications as drug carriers for diagnostic and therapeutic purposes in laboratory animals, but the translation of animal results to clinical success is low. Currently, this field is confronting a dilemma of ?so many publications but very few drugs?. There are multiple factors contributing to this. One important factor is a lack of a robust model that can integrate available experimental data to simulate target organ dosimetry and extrapolate pharmacokinetics of gold nanoparticles across different exposure scenarios. Another critical factor is that the traditional pharmacokinetic analysis approaches currently used for small molecules (e.g., drugs and environmental chemicals) are used for nanoparticles, which may not be appropriate because of differences in the pharmacokinetics between small molecules and nanoparticles. Built upon the extensive pharmacokinetic datasets for different sizes of gold nanoparticles in rats after different routes of administration (i.e., intravenous injection, oral gavage, inhalational exposure, or intratracheal instillation) from our collaborator?s laboratory and based on our recently published physiologically based pharmacokinetic (PBPK) model for gold nanoparticles after single route of intravenous administration, here we propose a multi-route whole-body PBPK modeling strategy to address these challenges. The objective of this proposal is to determine whether the traditional route-to-route extrapolation approaches of PBPK models for small molecules are appropriate for gold nanoparticles. We hypothesize that the traditional route-to-route extrapolation approaches of PBPK models for small molecules may not be appropriate for gold nanoparticles. Two Specific Aims were formulated to test this hypothesis. Aim 1: To develop a multi-route PBPK model for gold nanoparticles using traditional PBPK modeling approaches that are typically used for small molecules. Aim 2: To develop a multi- route PBPK model for gold nanoparticles using a new approach particularly designed for nanoparticles. This project is novel and significant because the route-to-route extrapolation of nanoparticle pharmacokinetics has not been rigorously and quantitatively tested before and represents a critical barrier in the field. The proposed research has broad impacts because: (1) if the aims are achieved and our hypothesis is true, then it will establish a rational approach for conducting route-to-route extrapolation that is specifically for nanoparticles; (2) if the results suggest that our hypothesis is false, then at minimal a new robust multi-route PBPK model will be established and our results will greatly improve our fundamental understanding of route-dependent tissue distribution of gold nanoparticles; (3) the proposed PBPK models will be converted to a graphical user interface (GUI) that will be shared with other researchers, thereby making a wide impact in the field by allowing researchers not fully versed in PBPK model coding to be able to use the models to make quantitative simulations and extrapolations. The availability of our collaborator?s extensive datasets and our recently published PBPK modeling framework makes this proposal highly feasible and ideally suitable for the R03 program.